Summary Localized prostate cancer can be treated in 5 sessions using a precise, targeted form of radiation known as stereotactic body radiation therapy (SBRT), with low toxicity. Despite these advances, overall outcomes for aggressive (high risk) prostate cancer remain poor, with 10-year recurrence-free survival of approximately 65% regardless of treatment modality. Recurrences are typically distant and carry poor prognosis, with 5 year survival of 25%. We propose to utilize the latest advances in cancer imaging (PSMA Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MR)) and radiation delivery (MR-guided radiation therapy with real-time adaptive planning), to deliver a personalized radiation treatment that targets the areas of greatest risk of recurrence in the prostate with improved precision, and as a result improve clinical outcomes for individuals with high risk prostate cancer. PSMA PET/MR is a novel imaging modality, not yet widely available, that augments the tissue detail provided by MR. The combination of PSMA PET with MR results in improved delineation of intraprostatic nodules and higher diagnostic accuracy for detection of metastatic disease compared to conventional imaging. PSMA PET/MR imaging data is readily transferable to a MR-based linear accelerator (MR-LINAC), a novel, innovative platform that allows direct visualization of the tumor during treatment, and permits real-time individualized correction for motion with online adaptive radiation planning. Through incorporation of superior pre-treatment imaging, enhanced identification of high risk intraprostatic nodules at greatest risk of recurrence, and precise MR-guided real-time adaptive delivery of radiation, we hypothesize that local and distant recurrences can be reduced. We will also utilize PSMA PET/MR and biopsy at 1 year after SBRT to characterize treatment response and detect disease recurrences earlier. To test our hypotheses, we will conduct a single arm, phase II clinical trial utilizing PSMA PET/MR guided SBRT with targeted dose-escalation to dominant intraprostatic nodule(s) on an MR-LINAC. The overarching scope of this proposal is to harness advanced PET and MR-based imaging and treatment to enhance the therapeutic index of SBRT in high risk prostate cancer, maximizing treatment efficacy while minimizing toxicity. If successful, this proposal will guide utilization of emerging imaging technologies (PSMA PET/MR and MR-LINACs are expected to increase in availability and usage over the next several years) and introduce a novel treatment paradigm with the potential to significantly improve prostate cancer outcomes.